Major depression is a serious health problem affecting more than 5% of the population, with a life-time prevalence of 15-20%.
Selective serotonin reuptake inhibitors have produced significant success in treating depression and related illnesses and have become among the most prescribed drugs. They nonetheless have a slow onset of action, often taking several weeks to produce their full therapeutic effect. Furthermore, they are effective in fewer than two-thirds of patients.
Serotonin selective reuptake inhibitors (SSRIs) are well known for the treatment of depression and other conditions. SSRIs work by blocking the neuronal reuptake of serotonin, thereby increasing the concentration of serotonin in the synaptic space, and thus increasing the activation of postsynaptic serotonin receptors.
However, although a single dose of an SSRI can inhibit the neuronal serotonin transporter which would be expected to increase synaptic serotonin, long-term treatment is required before clinical improvement is achieved.
It has been suggested that the SSRIs increase the serotonin levels in the vicinity of the serotonergic cell bodies and that the excess serotonin activates somatodendritic autoreceptors, 5HT1A receptors, causing a decrease in serotonin release in major forebrain areas. This negative feedback limits the increment of synaptic serotonin that can be induced by antidepressants.
A 5HT1A antagonist would limit the negative feedback and should improve the efficacy of the serotonin reuptake mechanism. (Perez, V., et al., The Lancet, 349:1594-1597 (1997)). Such a combination therapy would be expected to speed up the effect of the serotonin reuptake inhibitor.
Thus, it is highly desirable to provide improved compounds which both inhibit serotonin reuptake and which are antagonists of the 5HT1A receptor.
In accordance with this invention, there is provided a group of novel compounds of the formula: 
wherein
R1, R3, R4, R5 and R7 are, independently, hydrogen, halo, cyano, carboxamido, carboalkoxy of two to six carbon atoms, trifluoromethyl, alkyl of 1 to 6 carbon atoms, alkoxy of 1 to 6 carbon atoms, alkanoyloxy of 2 to 6 carbon atoms, amino, mono- or di-alkylamino in which each alkyl group has 1 to 6 carbon atoms, alkanamido of 2 to 6 carbon atoms, or alkanesulfonamido of 1 to 6 carbon atoms;
Y is Cxe2x95x90O or C(R2)2 and Z is CH2, CH2CH2, CHxe2x95x90CH or NR2, or Y and Z, taken together, form CR2xe2x95x90CH, Nxe2x95x90CR2 or CR2xe2x95x90N;
R2 and R6 are hydrogen or alkyl of 1 to 6 carbon atoms;
X is CR7 or N;
A dotted line represents an optional double bond; and
n is an integer 0, 1 or 2;
or a pharmaceutically acceptable salt thereof.
In some preferred embodiments of the present invention R1 is hydrogen, hydroxy, halogen, cyano, trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms. In still more preferred embodiments of the present invention R1 is hydrogen, halo or methoxy.
In other preferred embodiments of the present invention R2 is hydrogen or lower alkyl. Still more preferred are compounds of Formula I wherein R2 is hydrogen.
R3, R4 and R5 is are independently selected from hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms in some preferred embodiments of the present invention. R3, R4 and R5 are still more preferably selected from hydrogen, halogen or cyano.
R6 is preferably hydrogen or lower alkyl. R6 is still more preferably hydrogen.
Y is preferably C(R2)2, Z is preferably CH2, CH2CH2 or CHxe2x95x90CH or in other preferred embodiments Y and Z, taken together, form CR2xe2x95x90CH.
X is preferably CR7. When X is CR7, R7 is preferably hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms. Still more preferably R7 is hydrogen, halogen or cyano.
Still more preferred embodiments of the present invention are those in which R1 is hydrogen, hydroxy, halo, cyano, trifluoromethyl, alkyl of one to six carbon atoms or alkoxy of one to six carbon atoms; Y is Cxe2x95x90O or C(R2)2 and Z is CH2, CH2CH2 or CHxe2x95x90CH or Y and Z, taken together, form CR2xe2x95x90CH; R2 is hydrogen, or lower alkyl; R3, R4 and R5 are independently selected from hydrogen, hydroxy, halo, cyano, carboxamido, alkyl of one to six carbon atoms, or alkoxy of one to six carbon atoms; n is an integer 0 or 1; and R6 and the dotted line are defined as above.
Most preferred are those examples in which R1 is hydrogen, halo or methoxy, Y is C(R2)2 and Z is CH2, CH2CH2 or CHxe2x95x90CH or Y and Z, taken together, form CR2xe2x95x90CH; R2 is hydrogen; R3, R4 and R5 are independently selected from is hydrogen, halo or cyano, R6 is hydrogen, n is 0 and the dotted line in the azaheterocycle represents a double bond.
This invention relates to both the R and S stereoisomers of the aminomethyl-oxaheterocycle-fused-[1,4]-benzodioxan, as well as to mixtures of the R and S stereoisomers. Throughout this application, the name of the product of this invention, where the absolute configuration of the aminomethyl-oxaheterocycle-fused-[1,4]-benzodioxan is not indicated, is intended to embrace the individual R and S enantiomers as well as mixtures of the two. In some preferred embodiments of the present invention the S stereoisomer is preferred.
Where a stereoisomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer. Thus, an enantiomer substantially free of the corresponding enantiomer refers to a compound which is isolated or separated via separation techniques or prepared free of the corresponding enantiomer. Substantially free as used herein means that the compound is made up of a significantly greater proportion of one stereoisomer. In preferred embodiments the compound is made up of at least about 90% by weight of a preferred stereoisomer. In other embodiments of the invention, the compound is made up of at least about 99% by weight of a preferred stereoisomer. Preferred stereoisomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high performance liquid chromatography (HPLC) and the formation and crystallization of chiral salts or prepared by methods described herein. See, for example, Jacques, et al., Enantiomers, Racemates and Resolutions (Wiley Interscience, New York, 1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L. Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S. H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L. Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, IN 1972).
It is further recognized that tautomers of the claimed compounds may exist. The present invention thus encompasses tautomeric forms of compounds of the present invention.
Alkyl as used herein refers to an aliphatic hydrocarbon chain and includes straight and branched chains such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, and isohexyl. Lower alkyl refers to alkyl having 1 to 3 carbon atoms.
Alkanamido as used herein refers to the group Rxe2x80x94C(xe2x95x90O)xe2x80x94NHxe2x80x94 where R is an alkyl group of 1 to 5 carbon atoms.
Alkanoyloxy as used herein refers to the group Rxe2x80x94C(xe2x95x90O)xe2x80x94Oxe2x80x94 where R is an alkyl group of 1 to 5 carbon atoms.
Alkanesulfbnamido as used herein refers to the group Rxe2x80x94S(O)2xe2x80x94NHxe2x80x94 where R is an alkyl group of 1 to 6 carbon atoms.
Alkoxy as used herein refers to the group Rxe2x80x94Oxe2x80x94 where R is an alkyl group of 1 to 6 carbon atoms.
Carboxamido as used herein refers to the group xe2x80x94COxe2x80x94NH2.
Carboalkoxy as used herein refers to the group Rxe2x80x94Oxe2x80x94C(xe2x95x90O)xe2x80x94 where R is an alkyl group of 1 to 5 carbon atoms.
Halogen (or halo) as used herein refers to chlorine, bromine, fluorine and iodine.
Pharmaceutically acceptable salts are those derived from such organic and inorganic acids as: acetic, lactic, citric, cinnamic, tartaric, succinic, fumaric, maleic, malonic, mandelic, malic, oxalic, propionic, hydrochloric, hydrobromic, phosphoric, nitric, sulfuric, glycolic, pyruvic, methanesulfonic, ethanesulfonic, toluenesulfonic, salicylic, benzoic, and similarly known acceptable acids.
Specific compounds of the present invention are:
3-(1-{[8-methyl-2,3-dihydrofuro[2,3-f][1,4]benzodioxin-2-yl]methyl}-1,2,3,6-tetrahydro-4-pyridinyl)-1H-indole;
3-{1-[2,3,8,9-tetrahydrofuro[3,2-f][1,4benzodioxin-2-ylmethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole;
3-{1-[2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-ylmethyl]-1,2,3,6-tetrahydro-pyridin-4-yl}-1H-indole;
3-{1-[2,3,9,10-tetrahydro-8H-[1,4]dioxino[2,3-f]chromen-2-ylmethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole; and
5-fluoro-3-{1-[2,3,9,10-tetrahydro-8H-[1,4]dioxino[2,3-f]chromen-2-ylmethyl]-1,2,3,6-tetrahydro-4-pyridinyl}-1H-indole, and pharmaceutical salts thereof.
The 2-azaheterocyclylmethyl-furo[3,2-f][1,4]benzodioxans of this invention are prepared as illustrated below. Unless otherwise noted, the variables are as defined above. Specifically, the appropriately substituted 4-benzyloxysalicylaldehyde is alkylated with allyl bromide or chloride in the presence of a suitable base such as sodium hydride or potassium carbonate. The aldehyde moiety is then converted to a phenol via oxidation with meta-chloroperoxybenzoic acid (Baeyer-Villiger reaction), followed by cleavage of the resulting formate ester with methanol over basic alumina. The phenol thus obtained is then elaborated via alkylation with a glycidyl halide or tosylate in the presence of a base such as sodium hydride or potassium carbonate and the product submitted to a Claisen rearrangement in a refluxing high-boiling solvent such as mesitylene. Cyclization of the Claisen rearrangement product to the benzodioxan is effected via treatment with methanol and sodium bicarbonate. After conversion of the benzodioxan-2-methanol to the tosylate with p-toluene-sulfonyl chloride, diisopropylethylamine and catalytic dimethylaminopyridine, or to a halide via treatment with triphenylphosphine and carbon tetrabromide or chloride, the allyl side chain is cleaved to an aldehyde with sodium periodate and catalytic osmium tetroxide. Following reduction of the aldehyde to the alcohol with a suitable reducing agent such as tetra-n-butylammonium borohydride and removal of the benzyl protecting group with hydrogen over palladium on carbon, cyclization to the dihydrofuran is effected via a Mitsonobu reaction with triphenylphosphine and diethyl or diisopropylazodicarboxylate. 
Replacement of the halide or tosylate with the azaheterocyles appropriate to the invention via heating in a high boiling solvent such as dimethyl sulfoxide gives the title compounds of the invention in which the fused heterocycle is dihydrofuran. Alternatively, oxidation of the product of the Mitsonobu cyclization with an oxidant such as DDQ, followed by replacement of the halide or tosylate with the appropriate azaheterocycle gives the title compounds of the invention in which the fused heterocycle is furan. Reaction of the aldehyde mentioned above with an appropriate Grignard reagent (R2MgBr) gives the corresponding secondary alcohol, which after deprotection and cyclization as described above leads to compounds of the invention in which R2 is alkyl. Oxidation of the aldehyde mentioned above to the carboxylic acid, using an appropriate oxidant such as Jones"" reagent (CrO3/H2SO4), followed by deprotection as above and cyclization in acid leads to compounds of the invention in which Y is Cxe2x95x90O. Esterification of the carboxylic acid and treatment of the ester with excess Grignard reagent gives a tertiary alcohol, which upon deprotection as above and cyclization in acid leads to compounds of the invention in which the fused dihydrofuran is dialkylated.
The fused furan of the invention in which Ris methyl is alternatively prepared by the procedure outlined below in which the appropriately substituted 7-hydroxybenzodioxan-2-methanol is alkylated with 2,3-dichloro-1-propene in the presence of a suitable base such as sodium hydride and the Claisen rearrangement effected by refluxing in a high boiling solvent such as diethylaniline. The regioisomers thus obtained are separated by column chromatography on silica gel and 
the desired 8-(2-chloro-3-propene) derivative cyclized to the furan by treament with trifluoroacetic acid. Tosylation and replacement of the tosyl with the azaheterocycles appropriate to the invention gives the title compounds.
The fused pyrans of this invention are prepared as illustrated below. The 7-benzyloxy-8-allyl benzodioxan-2-methyltosylate described above is treated with borane in tetrahydrofuran, followed by oxidation with hydrogen peroxide to yield the 3-hydroxypropyl derivative. Deprotection of the phenol 
with hydrogen over palladium on carbon and cyclization with triphenylphosphine and diethyl or diisopropyl azodicarboxylate gives the unsubstituted pyran. Alternatively, oxidation of the alcohol with Jones"" reagent or any other suitable oxidant yields the carboxylic acid, which following deprotection as above is cyclized to the lactone by treatment with the appropriate acid. Esterification of the carboxylic acid and treatment of the ester with excess Grignard reagent gives the tertiary alcohol, which following deprotection as above and cyclization in acid gives the disubstituted pyran. As before, replacement of the tosylate with azaheterocycles appropriate to the invention gives the title compounds of the invention.
Unsaturated pyrans (chromenes) are prepared by the method outlined below. Specifically, the appropriately substituted 7-hydroxybenzodioxan-2-methyltosylate is alkylated with a suitable disubstituted propargyl halide (for example, 3-chloro-3-methyl-1-butyne) under the influence of a base such as potassium carbonate or with a disubstituted propargyl alcohol under the Mitsonobu conditions. The resulting ether is rearranged by refluxing in a high boiling solvent such as diethylaniline to give the chromene directly as a mixture of positional isomers. Separation of the regioisomers by column chromatography and replacement of the tosylate with the appropriate azaheterocycles gives the title compounds of the invention. 
The compounds of the invention in which the fused heterocycle is isoxazole are prepared as illustrated below. The 7-benzyloxy-8-allylbenzodioxan-2-methyltosylate described above is treated with bis(acetonitrile) palladium (II) chloride in refluxing methylene chloride or benzene in order to effect an isomerization of the double bond into conjugation with the aromatic ring. Cleavage of the olefin with osmium tetroxide and sodium periodate then gives the o-benzyloxybenzaldehyde, which is deprotected as above by treatment with hydrogen over palladium on carbon. Cyclization to the isoxazole is effected by treatment with hydroxylamine-O-sulfonic acid and sodium bicarbonate. Alternatively, the aldehyde may be treated with the appropriate Grignard reagent and the resulting secondary alcohol oxidized to a ketone with a suitable oxidant such as pyridinium chlorochromate or the Swern reagent. Deprotection as above and cyclization with hydroxylamine-O-sulfonic acid gives the alkyl substituted isoxazole. As before, replacement of the tosylate with azaheterocycles appropriate to the invention gives the title compounds of the invention. 
The compounds of the invention in which the fused heterocycle is oxazole are prepared as illustrated below. The o-benzyloxybenzaldehyde described above is treated with a suitable oxidant such as the Jones"" reagent (CrO3/H2SO4) to give the corresponding carboxylic acid. Treatment of the acid with diphenylphosphoryl azide and a tertiary base such as diisopropylethylamine in t-butanol effects a Curtius reaction and gives the corresponding aniline protected as the t-butoxycarbonyl (t-BOC) derivative. The t-BOC group is removed in an acid such as trifluoroacetic acid and cyclization to the oxazole is effected by refluxing in the appropriate ortho ester. As before, replacement of the tosylate with azaheterocycles appropriate to the invention gives the title compounds of the invention. 
The salicylaldehydes, benzodioxans and azaheterocycles appropriate to the above chemistry are known compounds or can be prepared by one schooled in the art. The compounds of the invention may be resolved into their enantiomers by conventional methods or, preferably, the individual enantiomers may be prepared directly by substitution of (2R)-(xe2x88x92)-glycidyl 3-nitrobenzenesulfonate or tosylate (for the S benzodioxan methanamine) or (2S)-(+)-glycidyl 3-nitrobenzenesulfonate or tosylate (for the R enantiomer) in place of epihalohydrin or racemic glycidyl tosylate in the procedures above.
Like the antidepressants fluoxetine, paroxetine and sertraline, the compounds of this invention have the ability to block the reuptake of the brain neurotransmitter serotonin. They are thus useful for the treatment of depression and other diseases commonly treated by the administration of serotonin selective reuptake inhibitor (SSRI) antidepressants, such as obsessive compulsive disorder, panic attacks, generalized anxiety disorder, social anxiety disorder, sexual dysfunction, eating disorders, obesity, addictive disorders caused by ethanol or cocaine abuse and related illnesses. Moreover, the compounds of this invention have affinity for and antagonist activity at brain 5-HT1A serotonin receptors. Recent clinical trials employing drug mixtures (eg, fluoxetine and pindolol) have demonstrated a more rapid onset of antidepressant efficacy for a treatment combining SSRI activity and 5-HT1A antagonism (Blier and Bergeron, 1995; F. Artigas et. al., 1996; M. B. Tome et. al., 1997). The compounds of the invention are thus exceedingly interesting and useful for treating depressive illnesses.
A protocol similar to that used by Cheetham et. al. (Neuropharmacol. 32:737, 1993) was used to determine the affinity of the compounds of the invention for the serotonin transporter. The compound""s ability to displace 3H-paroxetine from male rat frontal cortical membranes was determined using a Tom Tech filtration device to separate bound from free 3H-paroxetine and a Wallac 1205 Beta Plate(copyright) counter to quantitate bound radioactivity. Ki""s thus determined for standard clinical antidepressants are 1.96 nM for fluoxetine, 14.2 nM for imipramine and 67.6 nM for zimelidine. A strong correlation has been found between 3H-paroxetine binding in rat frontal cortex and 3H-serotonin uptake inhibition.
High affinity for the serotonin 5-HT1A receptor was established by testing the claimed compound""s ability to displace [3H] 8-OHDPAT (dipropylaminotetralin) from the 5-HT1A serotonin receptor following a modification of the procedure of Hall et al., J. Neurochem. 44, 1685 (1985) which utilizes CHO cells stably transfected with human 5-HT1A receptors. The 5-HT1A affinities for the compounds of the invention are reported below as Ki""s.
Antagonist activity at 5-HT1A receptors was established by using a 35S-GTPxcex3S binding assay similar to that used by Lazareno and Birdsall (Br. J. Pharmacol. 109: 1120, 1993), in which the test compound""s ability to affect the binding of 35S-GTPxcex3S to membranes containing cloned human 5-HT1A receptors was determined. Agonists produce an increase in binding whereas antagonists produce no increase but rather reverse the effects of the standard agonist 8-OHDPAT. The test compound""s maximum inhibitory effect is represented as the Imax, while its potency is defined by the IC50.
The results of the three standard experimental test procedures described in the preceding three paragraphs were as follows:
Hence the compounds of the present invention are combined serotonin reuptake inhibitors/5-HT1A antagonists and are useful for the treatment of diseases commonly treated by the administration of serotonin selective reuptake inhibitor (SSRI) antidepressants, such as depression (including but not limited to major depressive disorder, childhood depression and dysthymia), anxiety, panic disorder, post-traumatic stress disorder, premenstrual dysphoric disorder (also known as pre-menstrual syndrome), attention deficit disorder (with and without hyperactivity), obsessive compulsive disorder (including trichotillomania), social anxiety disorder, generalized anxiety disorder, obesity, eating disorders such as anorexia nervosa, bulimia nervosa, vasomotor flushing, cocaine and alcohol addiction, sexual dysfunction (including premature ejaculation), and related illnesses.
Thus the present invention provides methods of treating, preventing, inhibiting or alleviating each of the maladies listed above in a mammal, preferably in a human, the methods comprising providing a pharmaceutically effective amount of a compound of this invention to the mammal in need thereof.
Also encompassed by the present invention are pharmaceutical compositions for treating or controlling disease states or conditions of the central nervous system comprising at least one compound of Formula I, mixtures thereof, and or pharmaceutical salts thereof, and a pharmaceutically acceptable carrier therefore. Such compositions are prepared in accordance with acceptable pharmaceutical procedures, such as described in Remingtons Pharmaceutical Sciences, 17th edition, ed. Alfonoso R. Gennaro, Mack Publishing Company, Easton, Pa. (1985). Pharmaceutically acceptable carriers are those that are compatible with the other ingredients in the formulation and biologically acceptable.
The compounds of this invention may be administered orally or parenterally, neat or in combination with conventional pharmaceutical carriers. Applicable solid carriers can include one or more substances which may also act as flavoring agents, lubricants, solubilizers, suspending agents, fillers, glidants, compression aids, binders or tablet-disintegrating agents or an encapsulating material. In powders, the carrier is a finely divided solid which is in admixture with the finely divided active ingredient. In tablets, the active ingredient is mixed with a carrier having the necessary compression properties in suitable proportions and compacted in the shape and size desired. The powders and tablets preferably contain up to 99% of the active ingredient. Suitable solid carriers include, for example, calcium phosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, low melting waxes and ion exchange resins.
Liquid carriers may be used in preparing solutions, suspensions, emulsions, syrups and elixirs. The active ingredient of this invention can be dissolved or suspended in a pharmaceutically acceptable liquid carrier such as water, an organic solvent, a mixture of both or pharmaceutically acceptable oils or fat. The liquid carrier can contain other suitable pharmaceutical additives such as solubilizers, emulsifiers, buffers, preservatives, sweeteners, flavoring agents, suspending agents, thickening agents, colors, viscosity regulators, stabilizers or osmo-regulators. Suitable examples of liquid carriers for oral and parenteral administration include water (particularly containing additives as above e.g. cellulose derivatives, preferably sodium carboxymethyl cellulose solution), alcohols (including monohydric alcohols and polyhydric alcohols e.g. glycols) and their derivatives, and oils (e.g. fractionated coconut oil and arachis oil). For parenteral administration the carrier can also be an oily ester such as ethyl oleate and isopropyl myristate. Sterile liquid carriers are used in sterile liquid form compositions for parenteral administration.
Liquid pharmaceutical compositions which are sterile solutions or suspensions can be utilized by, for example, intramuscular, intraperitoneal or subcutaneous injection. Sterile solutions can also be administered intravenously. Oral administration may be either liquid or solid composition form.
Preferably the pharmaceutical composition is in unit dosage form, e.g. as tablets, capsules, powders, solutions, suspensions, emulsions, granules, or suppositories. In such form, the composition is sub-divided in unit dose containing appropriate quantities of the active ingredient; the unit dosage forms can be packaged compositions, for example packeted powders, vials, ampoules, prefilled syringes or sachets containing liquids. The unit dosage form can be, for example, a capsule or tablet itself, or it can be the appropriate number of any such compositions in package form.
The amount provided to a patient will vary depending upon what is being administered, the purpose of the administration, such as prophylaxis or therapy, and the state of the patient, the manner of administration, and the like. In therapeutic applications, compounds of the present invention are provided to a patient already suffering from a disease in an amount sufficient to cure or at least partially ameliorate the symptoms of the disease and its complications. An amount adequate to accomplish this is defined as a xe2x80x9ctherapeutically effective amount.xe2x80x9d The dosage to be used in the treatment of a specific case must be subjectively determined by the attending physician. The variables involved include the specific condition and the size, age and response pattern of the patient. Generally, a starting dose is about 5 mg per day with gradual increase in the daily dose to about 150 mg per day, to provide the desired dosage level in the human.
Provide as used herein means either directly administering a compound or composition of the present invention, or administering a prodrug, derivative or analog which will form an equivalent amount of the active compound or substance within the body.
The present invention includes prodrugs of compounds of Formula I. xe2x80x9cProdrugxe2x80x9d, as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to a compound of Formula I. Various forms of prodrugs are known in the art, for example, as discussed in Bundgaard, (ed.), Design of Prodrugs, Elsevier (1985); Widder, et al. (ed.), Methods in Enzymology, vol. 4, Academic Press (1985); Krogsgaard-Larsen, et al., (ed). xe2x80x9cDesign and Application of Prodrugs, Textbook of Drug Design and Development, Chapter 5, 113-191 (1991), Bundgaard, et al., Journal of Drug Deliver Reviews, 8:1-38(1992), Bundgaard, J. of Pharmaceutical Sciences, 77:285 et seq. (1988); and Higuchi and Stella (eds.) Prodrugs as Novel Drug Delivery Systems, American Chemical Society (1975).
The following examples illustrate the production of representative compounds of this invention.
To a solution of 1.36 g (7.47 mmole) of (2S)-(7-hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl)methanol in 50 mL of N,N-dimethylformamide was added 0.36 g (9.0 mmole) of 60% sodium hydride/mineral oil dispersion and the mixture stirred for 30 minutes at room temperature under nitrogen. Next 1.0 mL (11 mmole) of 2,3-dichloro-1-propene was added and the reaction heated at 60xc2x0 C. under nitrogen for 40 hours. The solvent was removed in vacuum and replaced with 200 mL of methylene chloride. The solution was washed with 50 mL of 0.1 N aqueous HCl and with water, dried over sodium sulfate, filtered and concentrated in vacuum to xcx9c2 g of a very dark oil. The oil was column chromatographed on silica gel with 20% hexane/methylene chloride and the product fractions combined and concentrated in vacuum to give 1.1 g of the (S)-enantiomer of the title compound as a pale yellow oil. 1H-NMR (d6-DMSO): doublet 7.76 xcex4 (1H); doublet 6.53 xcex4 (1H); doublet of doublets 6.45 xcex4 (1H); doublet 5.66 xcex4 (1H); doublet 5.48 xcex4 (1H); broad singlet 5.04 xcex4 (1H); singlet 4.6 xcex4 (2H); doublet of doublets 4.25 xcex4 (1H); multiplet 4.12 xcex4 (1H); doublet of doublets 3.92 xcex4 (1H); multiplet 3.6 xcex4 (2H).
A solution of 1.1 g (4.3 mmole) of {(2S)-7-[(2-chloro-2-propenyl)oxy]-2,3-dihydro-1,4-benzodioxin-2-yl}methanol in 60 mL of N,N-diethylaniline was refluxed under nitrogen for 15 hours. Upon cooling, the mixture was diluted with 250 mL of ethyl acetate and extracted eight times with 50 mL portions of 2 N aqueous HCl. It was then washed with 40 mL of saturated aqueous sodium bicarbonate and with 50 mL of saturated brine, dried over sodium sulfate, filtered and evaporated in vacuum to give 1.4 g of a black oil. This was column chromatographed on silica gel with 0.5% methanol in methylene chloride to give 0.40 g of the (S)-enantiomer of the title compound, as well as 0.39 g of 6-substituted Claisen product, both as pale yellow oils. 1H-NMR (d6-DMSO): singlet 9.05 xcex4 (1H); doublet 6.60 xcex4 (1H); doublet 6.30 xcex4 (1H); doublet 5.10 xcex4 (1H); multiplet 5.00 xcex4 (2H); doublet 4.85 xcex4 (1H); doublet of doublets 4.15 xcex4 (1H); multiplet 4.08 xcex4 (1H); doublet of doublets 3.90 xcex4 (1H); multiplet 3.55 xcex4 (2H); singlet 3.50 xcex4 (2H).
A solution of 0.40 g (1.6 mmole) of (3S)-5-(2-chloro-2-propenyl)-3-(hydroxymethyl)-2,3-dihydro-1,4-benzodioxin-6-ol in 70 mL of trifluoroacetic acid was stirred at room temperature for 26 hours. The solvent was then removed in vacuum and replaced with 100 mL of methanol. Potassium carbonate (3.0 g, 2.2 mmole) was added and the mixture stirred for an additional 1.5 hours at room temperature. The mixture was then filtered and the filtrate concentrated to a brown residue in vacuum. The residue was column chromatographed on silica gel with methylene chloride as eluant to give 0.20 g (60%) of the (S)-enantiomer of the title compound as a yellow oil. 1H-NMR (d6-DMSO): doublet 6.94 xcex4 (1H); doublet 6.71 xcex4 (1H); singlet 6.48 xcex4 (1H); triplet 5.07 xcex4 (1H); doublet of doublets 4.30 xcex4 (1H); multiplet 4.22 xcex4 (1H); multiplet 4.00 xcex4 (1H); multiplet 3.65 xcex4 (2H); singlet 2.38 xcex4 (3H).
To a solution of 0.20 g (0.90 mmole) of [(2S)-8-methyl-2,3-dihydrofuro[3,2-f][1,4]benzodioxin-2-yl]methanol in 5.0 mL of pyridine was added 1.0 g (5.2 mmole) of p-toluenesulfonyl chloride. The mixture was stirred at room temperature under nitrogen for 15 hours. The solvent was then removed in vacuum and replaced with 200 mL of methylene chloride. The solution was washed with 100 mL portions of 2 N aqueous HCl, saturated aqueous sodium bicarbonate and saturated brine, dried over magnesium sulfate, filtered and concentrated in vacuum to a brown residue. The residue was column chromatographed on silica gel with 1:1 methylene chloride/hexane as eluant and the product fractions combined and concentrated in vacuum to give 0.28 g of the (R)-enantiomer of the title compound as a pale yellow oil. 1H-NMR (CDCl3): doublet 7.79 xcex4 (2H); doublet 7.30 xcex4 (2H); doublet 6.86 xcex4 (1H); doublet 6.68 xcex4 (1H); singlet 6.29 xcex4 (1H); multiplet 4.48 xcex4 (1H); multiplet 4.26 xcex4 (3H); doublet of doublets 4.06 xcex4 (1H); singlet 2.43 xcex4 (3H); singlet 2.41 xcex4 (3H).